tbuckley/cabot-search huggingface dataset:
Machine learning generalizability across healthcare settings: insights from multi-site COVID-19 screening
Authors: Jenny Yang, Andrew A. S. Soltan, David A. Clifton
Journal: npj Digital Medicine (2022)

Abstract As patient health information is highly regulated due to privacy concerns, most machine learning (ML)-based healthcare studies are unable to test on external patient cohorts, resulting in a gap between locally reported model performance and cross-site generalizability. Different approaches have been introduced for developing models across multiple clinical sites, however less attention has been given to adopting ready-made models in new settings. We introduce three methods to do this—(1) applying a ready-made model “as-is” (2); readjusting the decision threshold on the model’s output using site-specific data and (3); finetuning the model using site-specific data via transfer learning. Using a case study of COVID-19 diagnosis across four NHS Hospital Trusts, we show that all methods achieve clinically-effective performances (NPV &gt; 0.959), with transfer learning achieving the best results (mean AUROCs between 0.870 and 0.925). Our models demonstrate that site-specific customization improves predictive performance when compared to other ready-made approaches.
MEDB-55. Single-cell transcriptomics reveals progenitor cells expressing a photoreceptor program as putative cells origin of MYC-driven Group 3 Medulloblastoma
Authors: Miao Zhao, Oliver Mainwaring, Gabriela Rosén, Ramy Elgendy, Milena Doroszko, Sanne Rijpkema, Anders Sundstrom, Sven Nelander, Holger Weishaupt, Takahisa Furukawa, Fredrik J Swartling
Journal: Neuro-Oncology (2022)

Abstract Brain tumors are the leading cause of childhood cancer-related death. Medulloblastoma is the most common malignant pediatric brain tumor with about 70% survival. Medulloblastoma comprises four distinct subgroups respective of genomic and molecular drivers influencing tumorigenesis. It has been established that despite being considered a single disease entity, each subgroup arises from a distinct population of cells found within unique compartments of the developing brain. The cell of origin of Group 3 medulloblastoma, the most malignant medulloblastoma subgroups, is currently unknown and remains controversial. Transcriptional profiling has revealed that Group 3 medulloblastomas are characterized by elevated expression of a photoreceptor program, which has not been described in the normal cerebellar development but is well characterized in the developing pineal gland and retinal. By investigating and comparing brain and tumor development between our previously developed medulloblastoma mice model (GMYC), where mice spontaneously develop Group 3 medulloblastoma after 4-6 months of age, and their control counterparts, we found that tumor cells emerged from progenitor cells where MYC overexpression drove the transformation of immature progenitor cells expressing a photoreceptor program. Our data suggest that MYC-driven Group 3 medulloblastoma originates from progenitor cells expressing a photoreceptor program, which has implications for future research and the development of novel treatments targeting this devastating childhood malignancy.
Immune cell differences between patients in different stages of monoclonal plasma cell disorders.
Authors: Christine Ho, Paul K. Wallace, Kristopher Attwood, Sarah Parker, Hemn Mohammadpour, Megan Herr, George Chen, Joseph Tario, Philip L. McCarthy, Jens Hillengass
Journal: Journal of Clinical Oncology (2022)

8065 Background: Multiple myeloma (MM) is an incurable plasma cell malignancy. Precursor conditions include monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM). Immune surveillance is paramount for keeping the malignancy in check, whereas a dysfunctional immune system is suspected to promote disease progression. Methods: We performed flow cytometric immune panel analyses including T-cell, B-cell, natural killer (NK) cell and dendritic cell (DC) subsets in MGUS, SMM, and MM patients between 2018-2021. Immune panels were analyzed on fresh peripheral blood samples drawn at diagnosis. The patient population were MGUS (n=28), SMM (n=19) and MM (n=94). Samples from MGUS and SMM patients were combined into a single group (asymptomatic) and were compared to MM patients (symptomatic). Lymphocytes were identified by CD45+ expression resolving against side-scattered light on a bivariate plot. B cell and NK cell antigen expression profiles were assessed from this lymphocyte population. T cell subsets were further determined by CD3+. The percent gated for each marker was summarized by cohort using the appropriate descriptive statistics and compared using the Mann-Whitney U exact test. Analyses were performed in SAS v9.4 (Cary, NC) using a two-sided α=0.05. Results: Compared to MGUS/SMM patients, MM patients had a significant lower proportion of naive B cells, NK cells, and cytolytic NK cells, and a significant higher proportion of cytolytic T cells at diagnosis (Table). Consistent with prior studies, we demonstrated an increase in exhaustion markers. There was a trend toward a higher population of CD8+ exhausted T cells in MM patients compared to MGUS/SMM patients. Since the follow up for this study was short, survival data is not mature. Conclusions: This study demonstrates the immune imbalance that occurs between myeloma precursor conditions and MM. There is a shift in certain cell subsets in the immune microenvironment that alters tumor immunosurveillance and tumor cell killing favoring disease progression. In data not shown, we are currently analyzing the bone marrow microenvironment and its relation to disease progression. Follow up studies could assess if therapeutic intervention could reverse the imbalance, restore homeostatic equilibrium with the goal of controlling disease long-term. [Table: see text]
Peripheral biomarkers to diagnose obstructive sleep apnea in adults: A systematic review and meta-analysis
Authors: Laetitia S. Gaspar, Ana Santos-Carvalho, Bárbara Santos, Catarina Carvalhas-Almeida, Ana Teresa Barros-Viegas, Bárbara Oliveiros, Helena Donato, Clara Santos, Joaquim Moita, Cláudia Cavadas, Ana Rita Álvaro
Journal: Sleep Medicine Reviews (2022)

Obstructive Sleep Apnea (OSA) has been recognized as a major health concern worldwide, given its increasing prevalence, difficulties in diagnosis and treatment, and impact on health, economy, and society. Clinical guidelines highlight the need of biomarkers to guide OSA clinical decision-making, but so far, without success. In this systematic review and meta-analysis, registered on the International Prospective Register of Systematic Reviews database (ID CRD42020132556), we proposed to gather and further explore candidates identified in the literature as potential OSA biomarkers. Search strategies for eight different databases (PubMed/Medline, Cochrane Library, Biblioteca Virtual da Saúde, Web of Science, EMBASE, World Intellectual Property Organization database, and bioRxiV and medRxiV Preprint Servers) were developed. We identified studies exploring potential biomarkers of OSA, in peripheral samples of adults, with and without OSA, with no comorbidities defined in study inclusion criteria, published after the last systematic review and meta-analysis conducted on OSA biomarkers, until May 31st, 2020. Risk of bias was assessed through the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. Demographic, clinical, and candidate biomarkers' data were collected and analyzed via random effects meta-analyses. Among the 1512 unique studies screened, 120 met the inclusion criteria and 16 studies with low risk of bias were selected for meta-analyses. The selected 16 studies enrolled a total of 2156 participants, from which 1369 were diagnosed with OSA and 787 were disease-free controls. The assessed variables showed high heterogeneity. From the 38 biomarker candidates evaluated, only two were evaluated in more than one study. Most studies pinpointed candidates with more potential for OSA prognosis. ADAM29, FLRT2 and SLC18A3 mRNA levels in PBMCs, Endocan and YKL-40 levels in serum, and IL-6 and Vimentin levels in plasma revealed the most promising candidates for OSA diagnosis. Although the current systematic review and meta-analysis allowed us to identify candidates to further explore as potential biomarkers in future studies, it is evident that OSA biomarkers research is still at an early stage. Most findings derive from small-size single-center study cohorts and single-candidate studies. We point several gaps in current OSA biomarker research that may guide into new directions and approaches towards the identification of OSA biomarkers.
Immunohistochemical analysis of buccal mucosa graft pathomorphosis following dorsal inlay transplantation in bulbar urethral stricture
Authors: V.V. Mitusov, O.V. Voronova, M.I. Kogan, Z.A. Mirzayev, V.P. Glukhov, B.G. Amirbekov, M.A. Akimenko
Journal: European Urology (2022)
Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer
Authors: Siqi Chen, Ping Xie, Matthew Cowan, Hao Huang, Horacio Cardenas, Russell Keathley, Edward J. Tanner, Gini F. Fleming, John W. Moroney, Alok Pant, Azza M. Akasha, Ramana V. Davuluri, Masha Kocherginsky, Bin Zhang, Daniela Matei
Journal: Journal of Clinical Investigation (2022)

BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.ResultsAmong 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR.ConclusionEpigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.Trial registrationClinicalTrials.gov NCT02901899.FundingUS Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.
Effectiveness and durability of benefit of mTOR inhibitors (mTORi) in a real-world cohort of metastatic prostate cancer (mPCA) patients with PI3K pathway alterations.
Authors: Corbin Eule, Thomas W. Flaig, Katy Ann Wong, Ryon Graf, Elaine T. Lam
Journal: Journal of Clinical Oncology (2022)

e17034 Background: Alterations in the PTEN/PI3K/AKT/mTOR pathway are prevalent in prostate cancer, as frequent as 41% by prospective comprehensive genomic profiling (CGP) (PMID: 31218271). The use of mTORi in unselected patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) has limited efficacy in inducing a PSA response or clinical response. In this retrospective study, we evaluated the clinical effectiveness of mTORi specifically in mPCA pts with tissue assessed PI3K pathway alterations. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine mPCA clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (̃800 sites of care). We evaluated treatment data for pts with mPCA from October 2014 to February 2020 and selected all pts who received mTORi therapy. Unique patients who received mTORi therapy were included if they had PI3K pathway alteration by tissue CGP. Demographic and clinical data were extracted and analyzed for PSA response and time to next treatment (TTNT) on mTORi therapy. Results: In a cohort of 2301 mPCA pts with 7208 evaluable treatment lines in the database, there were 20 pts who underwent mTORi treatment. After excluding 1 pt who had liquid CGP and 2 pts who did not have PI3K pathway alterations, we included 17 mPCA pts with tissue assessed PI3K pathway alterations who received mTORi treatment. Pts had a median age of 72y (IQR 68.0, 76.0) and were heavily pretreated (11 pts, 64.7% on 4th- or later-line therapy). Two pts (11.8%) were treated in first-line metastatic hormone-sensitive prostate cancer (mHSPC) setting and the remaining 15 pts (88.2%) had mCRPC. All 15 mCRPC pts received prior novel hormone therapy (NHT), and 10 pts (58.8%) were previously treated with a taxane. The PI3K pathway alterations included PTENdel (10 pts, 58.8%), AKT1mut (4 pts, 23.5%), PTENmut (2 pts, 11.8%), and dual PTENmut and PIK3CAmut (1 pt, 5.9%). Most (15 pts, 88.2%) were treated with everolimus (EVE) monotherapy; 1 pt received EVE + abiraterone (EVE/ABI); 1 pt had EVE + docetaxel (EVE/DOC). The median pre-treatment PSA (14 pts available) was 148.9 ng/dL (range 1.16, 3430). Among 10 pts with on treatment PSA available, 3 pts had PSA decrease at ̃ week 12 (range -0.1%, -44.0%) and 5 patients had PSA decrease overall. Only 1 pt (with PTEN homozygous deletion) had a PSA response with nadir -95.1% and TTNT of 7.5 months (mo). The median TTNT was 3.62 mo (range 0, 8.52). Interestingly, the ABI/EVE pt had PSA nadir -17.2% and TTNT 2.0 mo; the EVE/DOC pt had nadir of -21.9% and TTNT 7.5 mo. Conclusions: The clinical use of mTORi in patients with prostate cancer is low overall. In this small cohort of mPCA pts with tissue assessed PI3K pathway alterations, mTORi therapy was not effective with few PSA responses and short duration of therapy.
DIPG-21. DIPG cells alter the permeability of the blood-brain barrier in the brainstem leading to treatment failure.
Authors: Caitlin Ung, Dannielle H Upton, Pooja Venkat, Ruby Pandher, Flavio Curnis, Angelo Corti, Joesph Nicolazzo, Chelsea Mayoh, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2022)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive paediatric high-grade glioma with no effective therapies. The blood-brain barrier (BBB) presents a significant obstacle for delivery of therapeutics into the brain, especially in the brainstem. This study aims to investigate the effect of DIPG cells on the BBB in the brainstem. We hypothesized that the location of DIPG may result in a less permeable BBB than other brain regions. We compared two independent orthotopic models with the same DIPG cells injected in the cortical region or brainstem. We found that treatment with mTOR inhibitor, temsirolimus, significantly extended survival for cortical tumors compared with the same tumor in the brainstem (p=0.0097). Immunohistochemical analysis showed significant reduction of mTOR target, P-p70S6K, in the cortical region compared to brainstem in treated animals, with pharmacokinetic analysis confirming significantly higher temsirolimus levels in the cortical region. These findings suggest that cortical tumors respond better than brainstem tumors, and that a less permeable BBB in brainstem tumors contributes to treatment failure. To understand whether DIPG cells affect the BBB in the brainstem, single-cell RNA sequencing experiments were conducted on vasculature isolated from DIPG and matrigel-injected mice. Gene-ontology overrepresentation analyses identified downregulation in the P38MAPK pathway in endothelial cells from DIPG-injected mice, suggesting the potential for therapeutic manipulation with cytokines. Treatment with SNGR-TNFα, a derivative of an agent successfully used in improving drug penetration in CNS lymphoma patients, in an in vitro BBB/DIPG model significantly reduced transendothelial resistance, and further exploration into the effects on the BBB in vivo is currently being undertaken. Our studies indicate that the intact BBB in the brainstem in DIPG is a major reason for treatment failure, and DIPG cells directly influence the vasculature and response to treatment. This may lead to a novel DIPG treatment strategy and for other brain tumors.
Impact of depression among adolescents and young adults with cancer.
Authors: Edmund Men Qiao, Alexander Qian, David J Mariano, Terrence C. Lee, Eventine Youngblood, Linda Chou, James Don Murphy
Journal: Journal of Clinical Oncology (2022)

6549 Background: The incidence of adolescent and young adults (AYAs) with cancer continues to increase. The psychosocial burden of early cancer diagnosis within this unique AYA population remains poorly characterized. Without proper resources, these patients are likely to seek care in the acute care setting. For AYA patients, we evaluated the impact of malignancy on concurrent diagnosis with depression and on presenting to the emergency department (ED) with intentional self-injury. We further described the influence of concurrent depression diagnosis on hospital admission and extended length of stay (LOS) for AYA cancer patients. Methods: From the National Emergency Department Sample (NEDS), we identified patients between 15-39 years who presented to an ED in 2019. Diagnosis of cancer and depression were identified using International Classification of Diseases, 10th Revision coding. Separate multivariable logistic regressions evaluated the impact of cancer diagnosis on concurrent depression diagnosis and on presenting with intentional self-injury. For the subset of AYA cancer patients, multivariable logistic regressions evaluated the impact of depression on hospital admission and extended LOS ( &gt; 14 days). Results: We identified 10,570,148 AYA patients, and 35,035 had cancer (0.33%). Among AYA cancer patients, average age was 31 and the cohort skewed White (48.7%), female (58.1%), and with Medicaid insurance (48.4%). The prevalence of depression among AYA cancer patients was 9.6% vs. 4.4% for patients without cancer. On multivariable regression, AYA cancer patients had a 46% increased odds of depression diagnosis (odds ratio (OR), 95% confidence interval (CI): 1.46. [1.43-1.49] P &lt; 0.01) and 32% increased odds of intentional self-injury (OR, 95% CI: 1.32 [1.19-1.47] P &lt; 0.01) when compared to patients without cancer. Additional significant factors associated with depression diagnosis among AYA cancer patients were White race, female gender, and Medicaid insurance. Within AYA cancer patients, a concurrent diagnosis with depression was associated with ̃3-fold increased odds of hospital admission (OR, 95% CI: 3.02 [2.90-3.14] P &lt; 0.01) and a 31% increased odds of extended LOS (OR, 95% CI: 1.31 [1.23-1.39] P &lt; 0.01). Conclusions: From this national sample, we found a significant association between cancer diagnosis and depression within AYA patients, with cancer diagnosis also increasing the risk of intentional self-injury. Furthermore, AYA cancer patients diagnosed with depression had increased risk of both hospital admission and extended LOS. Our results underscore the potential gap in psychological care for AYA cancer patients and highlight the need for stronger mental health resources for this at-risk population.
A pan-cancer analysis of the granzyme family based on the TCGA database and single-cell RNA sequencing data.
Authors: Bin Xu, Junju He, Jing Li, Jie Wu, Huibo Zhang, Yan Jin, Yi Yao, Qibin Song
Journal: Journal of Clinical Oncology (2022)

e14580 Background: Human Granzymes (GZMs) are mainly regarded as protective cytotoxic proteases that block the development of cancer. This study aimed to systematically analyze the expression signature, immune infiltration pattern, predictive values of prognosis and immune response, and the biological process associated with GZMs in different cancers. Methods: We estimated the predictive values of GZMs in prognosis and drug sensitivities by Cox regression analysis, immunophenoscore (IPS) algorithm, etc. We identified potential factors associated with the expression of GZMs, involving the somatic mutation and copy number variation of driver genes. We further investigate the distributions of GZMs and their discrepancy in single-cell resolution. The package CellChat and SCENIC were used for cell-cell communications and regulatory network reconstruction respectively. The ssGSEA algorithm was used to calculate the GZMs score for a gene set of five granzymes and the enrichment score (ES) of regulons based on the bulk-seq data. We chose the specific regulons to cluster patients in pan-cancer. Results: In the immunotherapy context, the higher GZMs score was associated with better overall survival (OS) in urothelial carcinoma (HR = 0.31, p&lt; 0.01). In melanoma, the pooled HR value calculated by meta-analysis assay was 0.33 (95%CI: 0.189-0.58). In the single-cell resolution, we found the three patterns of GZMs expression in CD8+T/NK cells. Furthermore, we analyzed the discrepancy among different GZMs subtype cells in functions, cell-cell communications, and cell-type-specific regulons. In CD8+ Effector memory T cells, cluster 1 (GZMB+) and cluster 2 (GZMK+) exhibited different enriched pathways in adhesion, anti-bacteria, chemotaxis, migration, and metabolism. In the cell-cell communications analysis, the IFNG − (IFNGR1+IFNGR2) between CD8+ T cells and malignant cells was only significant in the C1 and C2 clusters. Pan-cancer patients were divided into five regulons clusters based on the regulons. Cluster 5 had the worst OS (HR = 8.49, 95%CI = 6.67-10.81, p&lt; 0.01) compared to cluster 1 which had the best prognosis. Cluster 5 had higher ES of regulons including Myb, Hmgb2, E2f7, E2f8, and lower ES of Egr3. Conclusions: In conclusion, the expressions of GZMs, GZMs score, and the specific regulons identified in this study were associated with the prognosis in pan-cancer patients. GZMs score was a valuable biomarker that can predict the response to immunotherapy. The patients who belong to different regulons subtypes have specific transcription factors, which may be potential targets for the precision medicine of anti-tumor strategies in pan-cancer.